TUMOUR IMMUNOLOGY

Presented By:

Payal GoyalM.Sc. Biotechnology (Sem-2)

ICG, Jaipur

Cancer immunology

Cancer immunology is the study of interactions between the immune system and cancer cells (also called tumors or malignancies). It is also a growing field of research that aims to discover innovative cancer immunotherapy's to treat and retard progression of this disease.

The immune response, including the recognition of cancer-specific antigens is of particular interest in this field as knowledge gained drives the development of new vaccines and antibody therapies.

Immunosurveillance and immunoediting the concept of cancer Immunosurveillance and immunoediting based on

(i) protection against development of spontaneous and chemically-induced tumors in animal systems.

(ii) identification of targets for immune recognition of human cancer.

ImmunosurveillanceCancer Immunosurveillance appears to be an important host protection

process that inhibits carcinogenesis and maintains regular cellular homeostasis . Testing of immune status in the diagnosis and therapy of cancer, immunoproliferative and immunodeficiency disorders, and autoimmune abnormalities. Changes in immune parameters are of special significance before, during and following organ transplantation. Strategies include measurement of tumor antigen and other markers (often by RADIOIMMUNOASSAY), studies of cellular or humoral immunity in cancer etiology, IMMUNOTHERAPY trials, etc.

ImmunoeditingImmunoediting is a process by which a person is protected from cancer growth and the development of tumour immunogenicity by their immune system. It has three main phases: elimination, equilibrium and escape. The elimination phase consists of the following four phases:

Elimination: Phase 1

The first phase of elimination involves the initiation of antitumor immune response. During this phase, the infiltrating lymphocytes such as the natural killer cells and T cells are stimulated to produce IFN-gamma.

Elimination: Phase 2

In the second phase of elimination, newly synthesized IFN-gamma induces tumour death (to a limited amount) as well as promoting the production of chemokines CXCL10, CXCL9 and CXCL11. These chemokines play an important role in promoting tumor death by blocking the formation of new blood vessels.

Elimination: Phase 3

In the third phase, natural killer cells and macrophages transactivate one another via the reciprocal production of IFN-gamma and IL-12. This again promotes more tumor killing by these cells via apoptosis and the production of reactive oxygen and nitrogen intermediates.

Elimination: Phase 4In the final phase of elimination, tumor-specific CD4+ and CD8+ T cells home to the tumor site and the cytolytic T lymphocytes then destroy the antigen-bearing tumor cells which remain at the site.Equilibrium and Escape

Tumor cell variants which have survived the elimination phase enter the equilibrium phase. In this phase, lymphocytes and IFN-gamma exert a selection pressure on tumor cells which are genetically unstable and rapidly mutating. Tumor cell variants which have acquired resistance to elimination then enter the escape phase. In this phase, tumor cells continue to grow and expand in an uncontrolled manner and may eventually lead to malignancies.

Tumor-associated antigens (TAA)

TAA are found on tumor cells and on normal cells during fetal life (onco-fetal

antigens), after birth in selected organs, or in many cells but at much lower

concentration than on tumor cells.

There are 2 main types of tumor antigens:

• Tumor-specific transplantation antigens (TSTA) which are unique to tumor

cells and not expressed on normal cells. They are responsible for rejection

of the tumor.

• Tumor associated transplantation antigens (TATA) that are expressed by

tumor cells and normal cells.

Tumor   Antigens

Antigen Antigen   Function Expressed   On

Cyclin-dependent kinase 4 Cell cycle regulator Melanoma

-catenin Signal transduction Melanoma

Caspase-8 Apoptosis regulator Squamous cell carcinoma

MAGE-1MAGE-3

Normal testicular proteinsMelanoma, breast, glioma

tumors;

Tyrosinase Melanin synthesis Melanoma

Surface Ig idiotype BCR Lymphoma

Her-2/neu Receptor tyrosine kinase Breast and ovarian cancer

MUC-1 Underglycosylated mucin Breast and pancreatic tumors

HPV E6 and E7 Viral gene products Cervical carcinoma

IMMUNITY AGAINST TUMORSThere is many evidence for anti-tumor immune reactivity in humans, evidence

for immunity against malignancy comes mostly from experimental studies with animals.

Immunotherapy

Immunotherapy has been used as a novel means of treating cancer. Both

active and passive means of stimulating the non-specific and specific

immune systems have been employed, in some cases with significant

success.

Active Immunotherapy

In this, the host actively participates in mounting an immune response.

Specific activation is achieved by using vaccine.

Passive Immunotherapy

This involves transfer of preformed antibodies, immune cells and other

factors into the hosts.

Immunotherapy of tumors

active

non-specific

BCG, Propionibacterium acnes, levamisole, cytokine genes, etc.

specifickilled tumor cells or their extract, recombinant antigens, idiotype, co-stimulatory molecule genes, etc.

passive

nonspecific LAK cells, cytokines

specificantibodies alone or coupled to drugs, pro-drug toxins or radioisotope; bispecific antibodies; T-cells

combined LAK cells and bispecific antibody

ChemotherapyTargeted carrier systems for drug delivery  

Many chemotherapeutics are characterized by a limited therapeutic efficacy, often due to

severe side effects at higher doses and rapid elimination from the body due to their

small size. Encapsulation of small therapeutic molecules into Nano particular carrier

systems, such as liposome or polymers, can improve the pharmacokinetic and

pharmacodynamics properties and protects the active compound from degradation.

Furthermore, equipping these carrier systems with target cell specific ligands

increases selectivity and efficacy.

Biotherapy

Cytotoxic fusion proteins    

• The direct fusion of effecter molecules to ligands.

• allows for the generation of targeted cytotoxic molecules.

• Using different ligands against vascular structures fused to effecter

molecules such as toxins or cytokines we plan to develop novel vascular

targeting agents.

• This process allow for analyze their efficacy, selectivity and safety in animal

models.